C11 oxymyl and hydroxylamino prostaglandins useful as FP agonists

ABSTRACT

The invention provides novel prostaglandin analogs. In particular, the present invention relates to compounds having a structure according to formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W, X, Z, a, b, p and q are defined below. This invention also includes optical isomers, diastereomers and enantiomers of formula (I), and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof. The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as bone disorders and glaucoma. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for bone disorders and glaucoma using these compounds or the compositions containing them.

This application is a 371 of PCT/IB99/00498, filed Mar. 22, 1999 whichclaims benefit of 60/080,075, filed Mar. 31, 1998.

TECHNICAL FIELD

The subject invention relates to certain novel analogs of the naturallyoccurring prostaglandins. Specifically, the subject invention relates tonovel Prostaglandin F analogs. The subject invention further relates tomethods of using said novel Prostaglandin F analogs. Preferred usesinclude methods of treating bone disorders and glaucoma.

BACKGROUND OF THE INVENTION

Naturally occurring prostaglandins (PGA, PGB, PGE, PGF, and PGI) areC-20 unsaturated fatty acids. PGF_(2a), the naturally occurringProstaglandin F in humans, is characterized by hydroxyl groups at the C₉and C₁₁ positions on the alicyclic ring, a cis-double bond between C₅and C₆, and a trans-double bond between C₁₃ and C₁₄. Thus PGF_(2a) hasthe following formula:

Analogs of naturally occurring Prostaglandin F have been disclosed inthe art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra andJohnson on May 17, 1977; German Pat. No. DT-002,460,990 issued to Beck,Lerch, Seeger, and Teufel published on Jul. 1, 1976; U.S. Pat. No.4,128,720 issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat.No. 4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8,1977; U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4,1973; P. W. Collins and S. W. Djuric, “Synthesis of TherapeuticallyUseful Prostaglandin and Prostacyclin Analogs”, Chem. Rev. Vol. 93(1993), pp. 1533-1564; G. L. Bundy and F. H. Lincoln, “Synthesis of17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG₁ Series”,Prostaglandins, Vol. 9 No. 1 (1975), pp. 1-4; W. Bartman, G. Beck, U.Lerch, H. Teufel, and B. Scholkens, “Luteolytic Prostaglandins:Synthesis and Biological Activity”, Prostaglandins, Vol. 17 No. 2(1979), pp. 301-311; C. liljebris, G. Selen, B. Resul, J. Stemschantz,and U. Hacksell, “Derivatives of 17- Phenyl-18,19,20-trinorprostaglandinF₂α Isopropyl Ester: Potential Antiglaucoma Agents”, Journal ofMedicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.

Naturally occurring prostaglandins are known to possess a wide range ofpharmacological properties. For example, prostaglandins have been shownto: relax smooth muscle, which results in vasodilatation andbronchodilatation, to inhibit gastric acid secretion, to inhibitplatelet aggregation, to reduce intraocular pressure, and to inducelabor. Although naturally occurring prostaglandins are characterized bytheir activity against a particular prostaglandin receptor, theygenerally are not specific for any one prostaglandin receptor.Therefore, naturally-occurring prostaglandins are known to cause sideeffects such as inflammation, as well as surface irritation whenadministered systemically. It is generally believed that the rapidmetabolism of the naturally occurring prostaglandins following theirrelease in the body limits the effects of the prostaglandin to a localarea. This effectively prevents the prostaglandin from stimulatingprostaglandin receptors throughout the body and causing the effects seenwith the systemic administration of naturally occurring prostaglandins.

Prostaglandins, especially prostaglandins of the E series (PGE), areknown to be potent stimulators of bone resorption. PGF_(2a) has alsobeen shown to be a stimulator of bone resorption but not as potent asPGE₂. Also, it has been demonstrated that PGF_(2a) has little effect onbone formation as compared to PGE₂. It has been suggested that some ofthe effects of PGF_(2a) on bone resorption, formation and cellreplication may be mediated by an increase in endogenous PGE₂production.

In view of both the wide range of pharmacological properties ofnaturally occurring prostaglandins and of the side effects seen with thesystemic administration of these naturally occurring prostaglandins,attempts have been made to prepare analogs to the naturally occurringprostaglandins that are selective for a specific receptor or receptors.A number of such analogs have been disclosed in the art. Though avariety of prostaglandin analogs have been disclosed, there is acontinuing need for potent, selective prostaglandin analogs for thetreatment of a variety diseases and conditions.

SUMMARY OF THE INVENTION

The invention provides novel PGF analogs. In particular, the presentinvention relates to compounds having a structure according to thefollowing formula:

wherein R₁, R₂, R₃, R₄, R₅, R6, W, X, Z, a, b, p, and q are definedbelow.

This invention also includes optical isomers, diastereomers andenantiomers of the formula above, and pharmaceutically-acceptable salts,biohydrolyzable amides, esters, and imides thereof.

The compounds of the present invention are useful for the treatment of avariety of diseases and conditions, such as bone disorders and glaucoma.Accordingly, the invention further provides pharmaceutical compositionscomprising these compounds. The invention still further provides methodsof treatment for bone disorders and glaucoma using theses compounds orthe compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

Terms and Definitions

“Acyl” is a group suitable for acylating a nitrogen atom to form anamide or carbamate or an oxygen atom to form an ester group. Preferredacyl groups include benzoyl, acetyl, tert-butyl acetyl, para-phenylbenzoyl, and trifluoroacetyl. More preferred acyl groups include acetyland benzoyl. The most preferred acyl group is acetyl.

“Alkyl” is a saturated or unsaturated hydrocarbon chain having 1 to 18carbon atoms, preferably 1 to 12, more preferably 1 to 6, morepreferably still 1 to 4 carbon atoms. Alkyl chains may be straight orbranched. Preferred branched alkyl have one or two branches, preferablyone branch. Preferred alkyl are saturated. Unsaturated alkyl have one ormore double bonds and/or one or more triple bonds. Preferred unsaturatedalkyl have one or two double bonds or one triple bond, more preferablyone double bond. Alkyl chains may be unsubstituted or substituted withfrom 1 to 4 substituents. Preferred substituted alkyl are mono-, di-, ortrisubstituted. The substituents may be lower alkyl, halo, hydroxy,aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclicaromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocycliccarbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, andamino.

“Lower alkyl” is an alkyl chain comprised of 1 to 6, preferably 1 to 4carbon atoms.

“Aromatic ring” is an aromatic hydrocarbon ring system. Aromatic ringsare monocyclic or fused bicyclic ring systems. Monocyclic aromatic ringscontain from about 5 to about 10 carbon atoms, preferably from 5 to 7carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring.Bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9or 10 carbon atoms in the ring. Aromatic rings may be unsubstituted orsubstituted with from 1 to 4 substituents on the ring. The substituentsmay be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy orany combination thereof. Preferred substituents include halo andhaloalkyl. Preferred aromatic rings include naphthyl and phenyl. Themost preferred aromatic ring is phenyl.

“Bone disorder” means the need for bone repair or replacement.Conditions in which the need for bone repair or replacement may ariseinclude: osteoporosis (including post menopausal osteoporosis, male andfemale senile osteoporosis and corticosteroid induced osteoporosis),osteoarthritis, Paget's disease, osteomalacia, multiple myeloma andother forms of cancer, prolonged bed rest, chronic disuse of a limb,anorexia, microgravity, exogenous and endogenous gonadal insufficiency,bone fracture, non-union, defect, prosthesis implantation and the like.

“Carbocyclic aliphatic ring” is a saturated or unsaturated hydrocarbonring. Carbocyclic aliphatic rings are not aromatic. Carbocyclicaliphatic rings are monocyclic, or are fused, Spiro, or bridged bicyclicring systems. Monocyclic carbocyclic aliphatic rings contain from about4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, andmost preferably from 5 to 6 carbon atoms in the ring. Bicycliccarbocyclic aliphatic rings contain from 8 to 12 carbon atoms,preferably from 9 to 10 carbon atoms in the ring. Carbocyclic aliphaticrings may be unsubstituted or substituted with from 1 to 4 substituentson the ring. The substituents may be halo, cyano, alkyl, heteroalkyl,haloalkyl, phenyl, phenoxy or any combination thereof. Preferredsubstituents include halo and haloalkyl. Preferred carbocyclic aliphaticrings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. More preferred carbocyclic aliphatic rings includecyclohexyl, cycloheptyl, and cyclooctyl.

“Halo” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro,chloro and bromo; more preferred are chloro and fluoro, especiallyfluoro.

“Haloalkyl” is a straight, branched, or cyclic hydrocarbon substitutedwith one or more halo substituents. Preferred haloalkyl are C₁-C₁₂; morepreferred are C₁-C₆; more preferred still are C₁-C₃. Preferred halosubstituents are fluoro and chloro. The most preferred haloalkyl istrifluoromethyl.

“Heteroalkyl” is a saturated or unsaturated chain containing carbon andat least one heteroatom, wherein no two heteroatoms are adjacent.Heteroalkyl chains contain from 1 to 18 member atoms (carbon andheteroatoms) in the chain, preferably 1 to 12, more preferably I to 6,more preferably still 1 to 4. Heteroalkyl chains may be straight orbranched. Preferred branched heteroalkyl have one or two branches,preferably one branch. Preferred heteroalkyl are saturated. Unsaturatedheteroalkyl have one or more double bonds and/or one or more triplebonds. Preferred unsaturated heteroalkyl have one or two double bonds orone triple bond, more preferably one double bond. Heteroalkyl chains maybe unsubstituted or substituted with from 1 to 4 substituents. Preferredsubstituted heteroalkyl are mono-, di-, or trisubstituted. Thesubstituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy),acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g.,phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclicaliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.

“Heteroaromatic ring” is an aromatic ring system containing carbon andfrom 1 to about 4 heteroatoms in the ring. Heteroaromatic rings aremonocyclic or fused bicyclic ring systems. Monocyclic heteroaromaticrings contain from about 5 to about 10 member atoms (carbon andheteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 inthe ring. Bicyclic heteroaromatic rings contain from 8 to 12 memberatoms, preferably 9 or 10 in the ring. Heteroaromatic rings may beunsubstituted or substituted with from 1 to 4 substituents on the ring.The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl,phenyl, phenoxy or any combination thereof. Preferred substituentsinclude halo, haloalkyl, and phenyl. Preferred heteroaromatic ringsinclude thienyl, thiazolo, purinyl, pyrimidyl, pyridyl, and furanyl.More preferred heteroaromatic rings include thienyl, furanyl, andpyridyl. The most preferred heteroaromatic ring is thienyl.

“Heteroatom” is a nitrogen, sulfur, or oxygen atom. Groups containingmore than one heteroatom may contain different heteroatoms.

“Heterocyclic aliphatic ring” is a saturated or unsaturated ringcontaining carbon and from 1 to about 4 heteroatoms in the ring, whereinno two heteroatoms are adjacent in the ring and no carbon in the ringthat has a heteroatom attached to it also has a hydroxyl, amino, orthiol group attached to it. Heterocyclic aliphatic rings are notaromatic. Heterocyclic aliphatic rings are monocyclic, or are fused orbridged bicyclic ring systems. Monocyclic heterocyclic aliphatic ringscontain from about 4 to about 10 member atoms (carbon and heteroatoms),preferably from 4 to 7, and most preferably from 5 to 6 in the ring.Bicyclic heterocyclic aliphatic rings contain from 8 to 12 member atoms,preferably 9 or 10 in the ring. Heterocyclic aliphatic rings may beunsubstituted or substituted with from 1 to 4 substituents on the ring.The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl,phenyl, phenoxy or any combination thereof. Preferred substituentsinclude halo and haloalkyl. Preferred heterocyclic aliphatic ringsinclude piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl andpiperdyl.

“Phenyl” is a monocyclic aromatic ring which may or may not besubstituted with from about 1 to about 4 substituents. The substituentsmay be fused but not bridged and may be substituted at the ortho, metaor para position on the phenyl ring, or any combination thereof. Thesubstituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl,phenoxy or any combination thereof. Preferred substituents on the phenylring include halo and haloalkyl. The most preferred substituent is halo.The preferred substitution pattern on the phenyl ring is ortho or meta.The most preferred substitution pattern on the phenyl ring is meta.

Compounds

The subject invention involves compounds having the following structure:

In the above structure, R₁ is CO₂H, C(O)NHOH, CO₂R₇, CH₂OH, S(O)₂R₇,C(O)NHR₇, C(O)NHS(O)₂R₇, or tetrazole; wherein R₇ is alkyl, heteroalkyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, or monocyclic heteroaromatic ring.Preferred R₇ is methyl, ethyl, and isopropyl. Preferred R₇ is CO₂H,C(O)NHOH, CO₂R₇ C(O)NHS(O)₂R₇, and tetrazole. Most preferred R₁ is CO₂Hand CO₂R₇.

In the above structure, W is O, NH, S, S(O), S(O)₂, or (CH₂)_(m);wherein m is an integer from 0 to about 3. Preferred W is O and(CH₂)_(m). Most preferred W is (CH₂)₁.

In the above structure, R₂ is H and R₃ is H or lower alkyl, or R₂ and R₃together form a covalent bond.

In the above structure, R₄ is H, alkyl, heteroalkyl, monocycliccarbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring,monocyclic aromatic ring, or monocyclic heteroaromatic ring. PreferredR₄ is H and lower alkyl. Most preferred R₄ is H.

In the above structure, each R₅ is independently selected from the groupconsisting of H, CH₃, and C₂H₅. Preferred R₅ is H and CH₃. Mostpreferred R₅ is H.

In the above structure, X is NHR₈ or OR₈, wherein each R₈ isindependently selected from the group consisting of H, acyl, alkyl,heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclicheterocyclic aliphatic ring, monocyclic aromatic ring, and monocyclicheteroaromatic ring. Preferred R₈ is H. Preferred X is OR₈. Mostpreferred X is OH.

In the above structure, each R6 is independently selected from the groupconsisting of H, CH₃, C₂H₅, OR₈, NHR₈. Preferred R₆ is H, CH₃, C₂H₅,OR₈. Most preferred R₆ is H and CH₃.

In the above structure, Y is O, NHR₈, S, S(O), or S(O)₂, provided nocarbon has more than one heteroatom attached to it. Preferred Y is O,NHR₈, and S. Most preferred Y is O.

In the above structure, Z is H, methyl, monocyclic carbocyclic aliphaticring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring,or monocyclic heteroaromatic ring, bicyclic carbocyclic aliphatic ring,bicyclic heterocyclic aliphatic ring, bicyclic aromatic ring, orbicyclic heteroaromatic ring, provided that when Y is S, S(O), or S(O)₂and Z is H, q is at least 1. Preferred Z is monocyclic aromatic ring andmonocyclic heteroaromatic ring. More preferred Z is thienyl and phenyl.

In the above structure, a and b are independently selected from thegroup consisting of single bond, cis double bond, and trans double bond.Preferred a is single bond or cis double bond, and preferred b is singlebond or trans double bond.

In the above structure, p is an integer from 1 to 5, q is an integerfrom 0 to 5, and p+qis 1 to 5.

The invention also includes optical isomers, diastereomers andenantiomers of the above structure. Preferred stereochemistry at allstereocenters of the compounds of the invention mimic that of naturallyoccurring PGF_(2a).

It has been discovered that the novel PGF analogs of the subjectinvention are useful for treating bone disorders, especially those thatrequire a significant increase in bone mass, bone volume, or bonestrength. Surprisingly, the compounds of the subject invention have beenfound to provide the following advantages over known bone disordertherapies: (1) An increase trabecular number through formation of newtrabeculae; (2) An increase in bone mass and bone volume whilemaintaining a more normal bone turnover rate; and/or (3) An increase inbone formation at the endosteal surface without increasing corticalporosity.

In order to determine and assess pharmacological activity, testing ofthe subject compounds in animals is carried out using various assaysknown to those skilled in the art. For example, the bone activity of thesubject compounds can be conveniently demonstrated using an assaydesigned to test the ability of the subject compounds to increase bonevolume, mass, or density. An example of such assays is theovariectomized rat assay.

In the ovariectomized rat assay, six-month old rats are ovariectomized,aged 2 months, and then dosed once a day subcutaneously with a testcompound. Upon completion of the study, bone mass and/or density can bemeasured by dual energy x-ray absorptometry (DXA) or peripheralquantitative computed tomography (pQCT), or micro computed tomography(mCT). Alternatively, static and dynamic histomorphometry can be used tomeasure the increase in bone volume or formation.

Pharmacological activity for glaucoma can be demonstrated using assaysdesigned to test the ability of the subject compounds to decreaseintraocular pressure. Examples of such assays are described in thefollowing reference, incorporated herein: C. liljebris, G. Selen, B.Resul, J. Sternschantz, and U. Hacksell, “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F₂α Isopropyl Ester: PotentialAntiglaucoma Agents”, Journal of Medicinal Chemistry, Vol. 38 No. 2(1995), pp. 289-304.

Compounds useful in the subject invention can be made using conventionalorganic syntheses. Particularly preferred syntheses are the followingtwo general reaction schemes:

In Scheme 1, R₁, R₂, R₃, R₄, R₅, R₆, X, Y, p, q, and Z are as definedabove unless otherwise defined. The Methyl7[3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl] heptanoate (S1a) depicted asstarting material for Scheme 1 is commercially available (such as fromSumitomo Chemical or Cayman Chemical).

In the above Scheme 1, Methyl 7-[3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl]heptanoate (S1a) is reacted with a silylating agent and base in asolvent that will allow the silylation to proceed. Preferred silylatingagents include tert-butyldimethylsilyl chloride andtert-butyldimethylsilyl trifluoromethanesulphonate. The most preferredsilylating agent is tert-butyldimethylsilyl trifluoromethanesulphonate.Preferred bases include triethylamine, trimethylamine, and 2,6-lutidine.More preferred bases include triethylamine and 2,6-lutidine. The mostpreferred base is 2,6-lutidine. Preferred solvents include halocarbonsolvents with dichloromethane being the most preferred solvent. Thereaction is allowed to proceed at a temperature preferably between −100°C. and 100° C., more preferably between −80° C. and 80° C., and mostpreferably between −70° C. and 23° C.

The resulting silylated compound is isolated by methods known to thoseof ordinary skill in the art. Such methods include, but are not limitedto, extraction, solvent evaporation, distillation, and crystallization.Preferably, the silyl ether is purified after isolation by distillationunder vacuum.

The silylated compound is then reacted with the cuprate generated viaGrignard formation of the appropriate alkenyl bromide as disclosed, forexample, in the following references: H.O. House et. al., “The Chemistryof Carbanions: A Convenient Precursor for the Generation of LithiumOrganocuprates”, J. Org. Chem. Vol. 40 (1975) pp. 1460-69; and P.Knochel et. al., “Zinc and Copper Carbenoids as Efficient and Selectivea′/d′ Multicoupling Reagents”, J. Amer. Chem. Soc. Vol. 111 (1989) p.6474-76. Preferred alkenyl bromides include 4-bromo-1-butene,4-bromo-1-butyne, 4-bromo-2-methyl-1-butene, and4-bromo-2-ethyl-1-butene. The most preferred alkenyl bromide is4-bromo-1-butene. Preferred solvents include ethereal solvents, of whichdiethyl ether and tetrahydrofuran are preferred. The most preferredsolvent is tetrahydrofuran. The Grignard reagent is allowed to form at atemperature between 100° C. and 23° C., more preferably between 85° C.and 30° C., and most preferably between 75° C. and 65° C. The reactiontime is preferably between 1 hour and 6 hours, with a more preferredreaction time being between 2 hours and 5 hours, and the most preferredreaction time being between 3 hours and 4 hours.

Once the Grignard reagent is formed, the cuprate is generated from thealkenyl magnesium species. The temperature range for cuprate formationis between −100° C. and 0° C. The preferred temperature range is between−80° C. and −20° C. The more preferred temperature range is between −75°C. and −50° C. The preferred reaction time is between 30 minutes and 6hours. The more preferred reaction time is between 45 minutes and 3hours. The most preferred reaction time is between 1 hour and 1.5 hours.

The compound depicted as S1b is isolated by methods known to one ofordinary skill in the art. Such methods include, but are not limited to,extraction, solvent evaporation, distillation, and crystallization.Preferably, S1b is purified by flash chromatography on silica gel(Merck, 230-400 mesh) using 10% EtOAc/hexanes as the eluent.

S1b is then reacted with a hydride reducing agent and a polar, proticsolvent to give the C₉ alcohol. Preferred reducing agents includelithium aluminum hydride, sodium borohydride, and L-selectride. Morepreferred reducing agents include sodium borohydride, and L-selectride.The most preferred reducing agent is sodium borohydride. Preferredsolvents include methanol, ethanol, and butanol. The most preferredsolvent is methanol. The reduction is carried out at a temperaturebetween −100° C. and 23° C. The preferred temperature range is between−60° C. and 0° C. The most preferred temperature range is between −45°C. and −20° C.

The resulting alcohol of S1b is isolated by methods known to one ofordinary skill in the art. Such methods include, but are not limited to,extraction, solvent evaporation, distillation, and crystallization.Preferably, the alcohol is purified by flash chromatography on silicagel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.

The alcohol can be protected as described previously herein. Theprotected or unprotected alcohol is then treated withmeta-chloroperbenzoic acid in a halocarbon solvent to provide the novelepoxide intermediate depicted as S1c. Preferred halocarbon solventsinclude dichloromethane, dichloroethane, and chloroform. More preferredhalocarbon solvents are dichloromethane and dichloroethane. The mostpreferred halocarbon solvent is dichloromethane.

The compound depicted as S1c is isolated by methods known to one ofordinary skill in the art. Such methods include, but are not limited to,extraction, solvent evaporation, distillation, and crystallization.Preferably, S1c is purified by flash chromatography on silica gel(Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.

The intermediate epoxide depicted as S1c can be reacted with a varietyof oxygen, sulfur and nitrogen containing nucleophiles as disclosed, forexample, in J. G. Smith, “Synthetically Useful Reactants of Epoxides”,Synthesis (1984) p. 629-656, to provide the C₁₁-protected13,14-dihydro-15-substituted-16-tetranor prostaglandin F₁α derivatives.

With sulfur nucleophiles, the reaction is carried out preferably between150° C. and 0° C., more preferably between 120° C. and 20° C., and mostpreferably between 80° C. and 50° C. Preferred bases for the reactioninclude triethylamine, N.N diisopropylethylamine, and trimethylamine.The most preferred base is triethylamine. Preferred solvents for thereaction are aromatic hydrocarbon solvents. Preferred solvents includexylenes, toluene, and benzene. The most preferred solvent is benzene.With nitrogen and oxygen nucleophiles, preferred solvents includeethereal solvents and polar, protic solvents. More preferred etherealsolvents include diethyl ether, dibutyl ether and tetrahydrofuran. Themost preferred ethereal solvent is tetrahydrofuran. More preferredpolar, protic solvents include ethyl alcohol, methyl alcohol, andtert-butyl alcohol. The most preferred polar, protic solvent is ethylalcohol.

The ring-opening process with nitrogen and oxygen nucleophiles can becatalyzed with Lewis acids. Preferred Lewis acids include magnesiumperchlorate, trimethylsilyl trifluoromethanesulphonate, andtrimethylaluminum. The most preferred Lewis acid is magnesiumperchlorate. The reaction is carried out at a temperature between 150°C. and 23° C., preferably between 125° C. and 40° C., and morepreferably between 100° C. and 75° C.

The selective protection of C-9 and C-15 can be accomplished by methodsknown to one of ordinary skill in the art. Preferred protecting groupsinclude, but are not limited to acylating agents, alkylating agent, andcarbonate forming agents. The most preferred protecting group is acetyl.Preferred solvents include halohydrocarbon and amine solvents. The mostpreferred is pyridine. Preferred reagents include acetyl halides andacetic anhydride. The most preferred is acetic anhydride. Thetemperature range for the reaction is −100° C. to 100° C. The preferredrange is −10° C. to 40° C. More preferred range is −5° C. to 30° C. Thepreferred reaction time is 1 hour to 48 hours. More preferred is 6 hoursto 24 hours.

The compound depicted as S1d is isolated by methods known to one ofordinary skill in the art. Such methods include, but are not limited to,extraction, solvent evaporation, distillation, and crystallization.Preferably, S1d is purified by flash chromatography on silica gel(Merck, 230-400 mesh) using 10% EtOAc/hexanes as the eluent.

The resulting C-11 ether on compound S1d is deprotected using using afluoride equivalent. The deprotection reagents include tetrabutylammonium fluoride, hydrogen fluoride in pyridine, potassium fluoride,and treatment with strong acid. Preferred is HF/pyridine. Thetemperature range is −100° C. to 50° C. The preferred temperature rangeis −50° C. to 30° C. The most preferred is −20° C. to 10° C. Thepreferred solvents are THF, Acetonitrile, and Et₂O. Most preferred isacetonitrile.

The compound is isolated by methods known to one of ordinary skill inthe art. Such methods include, but are not limited to, extraction,solvent evaporation, distillation, and crystallization. Preferably thecompound is purified by flash chromatography on silica gel (Merck,230-400 mesh) using 20% EtOAc/hexanes as the eluent.

Compound S1e is produced by the oxidation of the C-11 alcohol to givethe ketone. The oxidation can be accomplished by, but are not limitedto, Swern, Jones, PCC, PDC. The most preferred is PCC. The mostpreferred solvent is dichloromethane. The preferred reaction temperatureis −30° C. to 100° C. The most preferred is 0° C. to 50° C. Compound S1eis isolated by methods known to one of ordinary skill in the art. Suchmethods include, but are not limited to, extraction, solventevaporation, distillation, and crystallization. Preferably the compoundis purified by filtering through Florcil and solvent evaporation.

Compound S1f is formed by the reaction of NH₂OR₄ in buffered solution ofsolvents. The preferred buffer is sodium acetate. The preferred solventratio is 3:1:1 (methanol:dioxane:water). The preferred temperature rangeis −20° C. to 100° C. The compound depicted as S1f is isolated bymethods known to one of ordinary skill in the art. Such methods include,but are not limited to, extraction, solvent evaporation, distillation,and crystallization. Preferably, S1f is purified by flash chromatographyon silica gel (Merck, 230-400 mesh) using 10% EtOAc/hexanes as theeluent.

Deprotection of S1f is accomplished by methods known to one of ordinaryskill in the art and yields compounds of Formula I. Compounds depictedby Formula I are exemplified in Examples 1-15.

Reduction of the oxime of S1f gives the compound S1h as the hydroxylamine. The reduction is accomplished by treatment with sodiumcyanoborohydride. The preferred solvent is MeOH. The preferredtemperature range is −100° C. to 100° C.

Deprotection of S1h is accomplished by methods known to one of ordinaryskill in the art and yields compounds of Formula II. Compounds depictedby Formula II are exemplified in Examples 29-34.

In Scheme 2, R₁, R₂, R₃, R₄, R₅, R₆ W, X, Z, and P are as defined aboveunless otherwise defined. The Corey Aldehyde (S2a) depicted as startingmaterial for Scheme 2 is commercially available (such as from AldrichChemical or Cayman Chemical).

In the above Scheme 2, Corey Aldehyde is commercially-available witheither a silyl group (P₁) or an ester group (P₁) attached to thealcohol. The preferred protecting groups includetert-butyldimethylsilyl, acetate, benzoate, and para-phenyl benzoate.The most preferred protecting group is tert-butyldimethylsilyl.

The Corey aldehyde (S2a) is first reacted with an aldehyde protectinggroup to make a ketal or acetal. Examples of this type of protection arefound in Greene and Wuts, Protecting Groups in Organic Synthesis, 2ded., Wiley & Sons, N.Y. 1991. In this case, especially preferred arecyclic ketals and acetals. The aldehyde (S2a) is reacted with theappropriate 1,2- diol and a suitable acidic catalyst. The solvent can bethe diol, and an anhydrous solvent, such as ether or dichloromethane.Particularly useful is 1,2-bis-TMS ethylene glycol to effect thistransformation in ether at room temperature.

The ketal-protected S2a may then undergo a routine ofprotection/deprotection if desired, to exchange the P₁ group for a moresuitable one, using procedures known in the art. Particularly useful isthe exchange of a silyl group for an acyl group, and vice versa. Alsouseful is the exchange of a silyl or acyl group for an o-bromo-benzylether group.

The compound (S2b) is then subjected to a DIBAL reduction to make thehemiacetal. This intermediate is not isolated but reacted as soon aspossible with a Wittig salt to form an alkene (S2c). Particularlypreferred Wittig salts are derived from omega bromo- four to five carbonstraight chain carboxylic acids and 3-oxocarboxylic acids. These areconveniently combined with triphenylphosphine in a suitable solvent toform the reactive Wittig salts. Other preferred reagents includestraight chain omega-bromo tetrazoles and primary nitriles.

The compound (S2c) is not isolated, but reacted crude with diazomethanein diethyl ether or, preferably, with TMS diazomethane in methanol togive S2d. In addition, a suitable protecting group may be placed on theC₉ alcohol at this time. The compound S2d is isolated by methods knownto one of ordinary skill in the art. Such methods include, but are notlimited to, extraction, solvent evaporation, distillation, andcrystallization. Preferably, it is purified by flash chromatography onsilica gel (Merck, 230-400 mesh) using 10% EtOAc/hexanes as the eluent.

The compound (S2d) is then optionally reduced at C-5,6 to give thesaturated alpha chain of the prostaglandin, if desired, or taken onwithout reduction. The cyclic ketal is removed with acid or acidic ionexchange resin in a suitable solvent to give the free aldehyde.Preferred solvents include THF/water mixtures.

The resulting aldehyde (S2e) is not isolated but reacted withketone-stabilized phosphonium salts. These are generally referred to as“Wadsworth-Horner-Erumons” reagents. This reaction requires a mild base.Examples of suitable bases include sodium carbonate or triethyl amine.The product ketone (S2f) is purified by methods known to one of ordinaryskill in the art. Such methods include, but are not limited to,extraction, solvent evaporation, distillation, and crystallization.Preferably, the ketone (S2f) is purified by flash chromatography onsilica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.

As seen in Scheme 2 above, the ketone (S2f) can be reacted in threeways. Reduction of the ketone with a reducing agent such as the Luchereagent, effects an alcohol at C-15, as illustrated by S2g.

At this point, the alcohols of S2g at C-9 and C-15 may be protected, ifneeded or desired. If so, the alcohols can be protected as describedpreviously herein. The S2g compound containing protected or unprotectedalcohols is then treated with a deprotecting agent to releaseselectively P₁ on C-11. Examples of such selective deprotectionreactions are given in Greene and Wuts.

Alternatively, when P₁ is the o-bromobenzyl ether, reduction of thebromine with a radical reducing agent such as (n-Bu)₃SnH will cause theradical-induced oxidation of C-11 to the ketone without needingprotection.

Compounds of the type S2h can be converted into compounds of Formula IIIand Formula IV. Compounds depicted by Formula III are exemplified inExamples 16-28. Compounds depicted by Formula IV are exemplified inExamples 35-40.

The ketone (S2f) can also be converted into compounds of the type S21.This occurs by the addition of suitable nucleophile to the ketone (S2f).Examples of nucleophiles include methyl magnesium bromide. Usingsubstantially the same techniques described above, the compounds of thetype S21 can be converted into compounds of Formula V, and compounds ofFormula V can be converted into compounds of Formula VI. Compoundsdepicted by Formula V are exemplified in Examples 41-43, and compoundsdepicted by Formula VI are exemplified in Example 44.

Compounds of the type S2f can also be reacted to give compounds of thetype S2m by reacting the ketone at C-15 with an active amine. Examplesof reactive amines include methyl amine and ethyl amine. The productscan be reduced or can react with nucleophiles using standard techniques,and the reduction can also extend to reduce the alkenes, if desired,using a reagent such as hydrogen gas over palladium on carbon.Alternatively, sodium cyanoborohydride will selectivity reduce the iminewithout disrupting the alkenes. Finally, a suitable nucleophile,preferably such as a methyl cerium reagent, can add to the imine.Addition of the methylcerium nucleophile (˜1.5 equiv.) is described inT. Imamoto, et al., “Carbon-Carbon Bond Forming Reactions Using CeriumMetal or Organocerium (III) Reagents”, J. Org. Chem. Vol. 49 (1984) p.3904-12; T. Imamoto, et al., “Reactions of Carbonyl Compounds withGrignard Reagents in the Presence of Cerium Chloride”, J. Am. Chem. Soc.Vol. 111 (1989) p. 4392-98; and references cited therein, gives theaminomethyl derivative. In that case, R₅ in compound S1n would be amethyl group.

Using the reactions disclosed above for compounds of the type S2h,compounds of Formula VII can be made from S2n. Compounds depicted byFormula VII are exemplified in Example 45. Compounds of the Formula VIIIcan thus be made from compounds of Formula VII. Compounds depicted byFormula VII are exemplified in Examples 46.

Compounds of Formula IX can be made from sulfonation orhydroxylamination of compounds of Formula III. Compounds depicted byFormula IX are exemplified in Examples 47-48.

These compounds are isolated by methods known to one of ordinary skillin the art. Such methods include, but are not limited to, extraction,solvent evaporation, distillation, and crystallization.

The following non-limiting examples illustrate the compounds,compositions, and uses of the present invention.

EXAMPLES

Compounds are analyzed using ¹H and ¹³C NMR, Elemental analysis, massspectra, high resolution mass spectra and/or IR spectra as appropriate.

Typically, inert solvents are used, preferably in dried form. Forexample, tetrahydrofuran (THF) is distilled from sodium andbenzophenone, diisopropylamine is distilled from calcium hydride and allother solvents are purchased as the appropriate grade. Chromatography isperformed on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merck)as appropriate. Thin layer chromatography analysis is performed on glassmounted silica gel plates (200-300 mesh; J. T. Baker) and visualizedusing uv light, 5% phosphomolybdic acid in EtOH, or ammoniummolybdate/cerric sulfate in 10% aqueous H₂SO₄.

Example 1

Preparation of 11-oximyl-13,14-dihydro-16-phenylthio-16tetranor PGD₁α(1j):

a. Methyl7-(2-oxo-4-(1,1,2,2-Tetramethyl-1-silapropoxy)cyclopent-1-enyl)Heptanoate (1a): To a solution ofMethyl-7-[3-(R)-hydroxy-5-oxo-1-cyclopenten-1-yl] heptanoate (1 equiv.)in CH₂Cl₂ at −78° C. is added 2,6 lutidine (1.3 equiv.) dropwise over 15minutes. The solution is kept at −78° C., and TBDMS Triflate (1.2equiv.) in CH₂Cl₂ is added dropwise over 15 minutes. The reaction iswarmed gradually to room temperature and stirred at room temperature for15 hours. Aqueous 10% HCl is added and the layers are separated. Thewater layer is extracted with CH₂Cl₂ and the organic layers arecombined. The organic layer is ished with brine, dried (Na₂SO₄) andconcentrated. The residue is distilled under vacuum (10 mm Hg) toprovide the silyl ether 1a as a yellow liquid.

b. Methyl7-(5-but-3-enyl-2-Hydroxy-4-(1,1,2,2-tetramethyl-1-silapropoxy)cyclopentyl) Heptanoate (1c): To a slurry of Mg⁰ powder (2 equiv.) inTHF at room temperature is added one crystal of 12 and 1-bromobutene (2equiv.) dropwise over 10 minutes. The reaction proceeds to exotherm asthe addition continues. After the addition is complete, the reaction isrefluxed for 3 hours and cooled to room temperature. The Grignard isdiluted with THF and added via cannula to a 3-necked flask equipped withmechanical stirring and charged with CuBr.DMS (2 equiv.) in a 1:1solution of THF/DMS at −78° C. After the addition of the Grignard (˜20min), the reaction is stirred for 1 hour at −78° C. The color of thereaction is dark red at this point. A solution of the ketone 1a (1equiv.) in THF is then added dropwise over 25 minutes. The reaction isstirred at −78° C. for 15 minutes, then allowed to warm slowly to roomtemperature over 2 hours. The reaction is quenched with aqueous NH₄Cland the excess DMS is allowed to evaporate overnight. The reaction ispartitioned between brine/CH₂Cl₂ and the layers are separated. Theaqueous layer is back-extracted with CH₂Cl₂ and the organic layers arecombined and dried (Na₂SO₄). The solvent is removed in vacuo and theresidue is chromatographed on SiO₂ (10% hexane/EtOAc) to give the ketone1b as a clear oil.

The ketone 1b (1 equiv.) is dissolved in MeOH and cooled to −40° C.Sodium borohydride (0.9 equiv.) is added portionwise over 10 minutes.After the addition is complete, the reaction is stirred for 13 hours at−40° C. and then for 12 hours at −78° C. The reaction is quenched withwater, partitioned between brine and CH₂Cl₂, and the layers separated.The aqueous layer is back-extracted with CH₂Cl₂ and the organic layersare combined and dried (Na₂SO₄). The solvent is removed in vacuo and theresidue chromatographed on SiO₂ (30% EtOAc/hexanes) to give the alcohol1c as a colorless oil.

c. Methyl7-(2-Hydroxy-5-(2-(2-oxiranyl)ethyl-4-(1,1,2,2-tetramethyl-1-sila-propoxy)cyclopentyl)Heptanoate (1d): The alcohol 1c (1 equiv.) is dissolved in CH₂Cl₂ andcooled to 0° C. Sodium bicarbonate is added, followed by m-CPBA (57%-85%purity) (3 equiv.) portionwise over 15 minutes. After the addition iscomplete, the reaction is stirred for 20 hours at room temperature. Thereaction is poured into water, partitioned between brine and CH₂Cl₂, andthe layers are separated. The aqueous layer is back-extracted withCH₂Cl₂ and the organic layers are combined and dried (Na₂SO₄). Thesolvent is removed in vacuo and the residue is chromatographed on SiO₂(20% EtOAc/hexanes) to give the epoxide diastereomers Id as a colorlessoil.

d. 13,14-Dihydro-16-phenylthio tetranor PGF₁α (1e): In a 5 mLround-bottomed flask, epoxide 1d (1 equiv.) and 100 uL of dry benzeneare added. The flask is cooled to 0° C., then is treated with 60 uL ofthiophenol (1.2 eq ) and 78 uL of triethyl amine (1.2 eq ) as disclosedin J. G. Smith, “Synthetically Useful Reactants of Epoxides”, Synthesis(1984) p. 629-656, and references cited therein. The ice bath is removedand the reaction is stirred at room temperature under nitrogenovernight. TLC is used to monitor the reaction. Excess thiophenol isadded if necessary. The reaction is quenched with brine and is extractedwith methylene chloride. The organic layer is ished three times with INHCl, brine, dried over sodium sulfate, and concentrated to yield 1e.

e. Methyl 9,15-Acetyl 13,14-dihydro-16-phenylthio tetranor PGF₁α (1g):In a 25 mL round-bottom flask, diol 1e (1 equiv.) and of aceticanhydride (2 mL ) is stirred in pyridine (10 mL) overnight. The reactionis concentrated under reduced pressure. The residue is dissolved indichloromethane (40 mL) and washed 2 times with 1 N HCl. The organiclayer is dried with MgSO₄ and solvent removed in vacuo leaving crude(1f).

The crude 1f is treated with HF/pyridine (6 equiv.) in dry acetonitrile(10 mL). The mixture is stirred at 0° C. for 2 hours and concentratedunder reduced pressure. The crude material is flashed on a silica gelcolumn using 30% ethyl acetate in hexane. Appropriate fractions werepooled and concentrated giving (1g) as a colorless oil.

f. Methyl 9,15-Acetyl 13,14-dihydro-16-phenylthio tetranor PGD₁α (1h):In a 50 mL round-bottom flask, alcohol 1g (1 equiv.) is added todichloromethane (20 mL) with 10 grams of powdered molecular sieves. PCC(3 equiv.) is then added, and the solution is stirred overnight. Themixture is filtered through Floracil and concentrated to a yellow oil(1h).

g. Methyl 9,15-acetyl 11-Oximyl-13,14-dihydro-16-phenylthio tetranorPGD₁α (1i): In a 25 mL round bottom flask is added ketone 1h (1 equiv.),sodium acetate (9 equiv.), and hydroxyl amine (2 equiv.); in 3:1:1(MeOH: dioxane: water) (5 mL). The solution is stirred overnight, andether (50 mL) is added. The organic layer is then washed with 1N HCl andbrine. The organic layer is then dried with MgSO₄ and concentrated underreduced pressure. The crude material is flashed on silica gel using 30%ethyl acetate in hexane. Appropriate fractions were collected andconcentrated to a yellow liquid (1i).

h. 11-Oximyl-13,14-dihydro-16-phenylthio-16-tetranor PGD₁α (1j): In a 15mL round-bottom flask is added 1i (1 equiv.), and LiOH (3 equiv.) in 3:1(THF:water). The mixture is stirred overnight and concentrated underreduced pressure. The residue is flashed on a silica gel column in 5%MeOH:dichloromethane with 0.1% acetic acid. Appropriate fractions werecombined, and concentrated to give a colorless oil (1j).

Examples 2-15

Examples 2-15 are prepared using substantially the same procedures asthose described in Example 1, substituting the appropriate startingmaterials. The skilled artisan may change temperature, pressure,atmosphere, solvents or the order of reactions as appropriate.Additionally, the skilled artisan may use protecting groups to blockside reactions or increase yields as appropriate. All such modificationscan readily be carried out by the skilled artisan in the art of organicchemistry, and thus are within the scope of the invention.

Example 2

11-Oximyl-13,14-dihydro-16-(2,4-difluorophenylthio)-16-tetranor-PGD₁Methyl Ester

Example 3

11-Oximyl-13,14-dihydro-16-(2,4-difluorophenoxy)-16-tetranor PGD₁

Example 4

11-Oximyl-13,14-dihydro-16-aza-17-(2,4-fluorophenyl)-17-trinor-PGD₁Methyl Ester

Example 5

11-Oximyl-13,14-dihydro-16-(4-fluorophenylthio)-16-tetranor PGD₁ EthylEster

Example 6

11-Oximyl-13,14-dihydro-16-(4-fluorophenoxy)-16-tetranor PGD₁

Example 7

11-Oximyl-13,14-dihydro-16-(3-chlorophenoxy)-16-tetranor PGD₁

Example 8

11-Oximyl-13,14-dihydro-16-methyl-16-(3-chlorophenoxy)-16tetranor PGD₁

Example 9

11-Oximyl-13,14-dihydro-16-(2-methoxyphenylthio)-16-tetranor PGD₁

Example 10

11-Oximyl-13,14-dihydro-16-(3-methoxyphenylthio)-16-tetranor PGD₁Isopropyl Ester

Example 11

11-Oximyl-13,14-dihydro-16-(thiomethyl-(2-thienyl))-16-tetranor PGD₁Methyl Ester

Example 12

11-Oximyl-13,14-dihydro-16-((3-trifluoromethyl)phenoxy)-16-tetranor PGD₁Methyl Ester

Example 13

11-Oximyl-13,14-dihydro-16-(2-methylphenoxy)-16-tetranor PGD₁ GlycerylEster

Example 14

11-Oximyl-13,14-dihydro-16-(3-methylphenylthio)-16-tetranor PGD₁

Example 15

11-Oximyl-13,14-dihydro-16-phenylthio-16-tetranor PGD₁ Methyl Ester

Example 16

Preparation of 11-Oximyl-16-(2-fluorophenoxy)-16-tetranor-PGD₂α (1n):

a. 7-Benzoyfoxy-6-(2,5-dioxolanyl)-2-oxabicyclo[3.3.0]octan-3-one (16b):In a round bottom flask equipped with a magnetic stir bar is placed1,2-bis(trimethylsilyloxy) ethane in methylene chloride at −78° C. Tothis is added, within 20 minutes, a solution of 16a in CH₂Cl₂. Thereaction is stirred for 1 hour at −78° C. and then slowly warmed to 25°C. for 1 hour. The reaction is quenched at 0° C. with water, extractedwith methylene chloride, is dried over MgSO₄, and is concentrated invacuo to give crude 16b (FW=318.32 g/mole).

b. 6-(2,5-Dioxolanyl)-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-one (16c): Toa well stirred solution of crude 16b (63.85 g, 201 mmol, 1 eq) inmethanol (786 m.L) at 0° C. is added a suspension of sodium methoxide(13.27 g, 246 mmol, 1.2 eq) in MeOH (98.3 mL). The reaction is stirredat 0° C. for 1 hour and then is warmed to 25° C. for 1 h. The reactionis neutralized with acidic ion exchange resin which has been washedthoroughly with MeOH (5×100 mL). The filtrate is concentrated in vacuoto give a syrup which is subjected to flash chromatography on silica geleluting with 4:1 hexane : ethyl acetate and 2% MeOH in CH₂Cl₂ to give16c as a yellow syrup.

c. 6-(2,5-Dioxolanyl)-2-oxa-7-(o-bromobenzyloxy) bicyclo [3.3.0]octan-3-one (16d): In a round bottom flask with a magnetic stir bar, isstirred a solution of 16c in CH₂Cl₂. To this solution is added dropwiseat −78° C. a suspension of NaH. The reaction is stirred for 30 minutesat −78° C. and then ortho-bromo benzyl bromide is added and the reactionis warmed to 25° C. overnight. The reaction is quenched with water (100mL). The organic layer is washed with water (3×100 mL), dried overMgSO₄, and concentrated in vacuo to give a yellow oil which is subjectedto flash chromatography on silica gel eluting with hexanes then 1% MeOHin CH₂Cl₂. The product is then washed with 1N HCl, 0.1N HCl, water andbrine to give 16d.

d. Methyl 7-(5-(2,5-Dioxolanyl)-2-hydroxy-4-(o-bromobenzyloxy)Cyclopentyl) hept-5-enoate (16f): In a round bottom flask with amagnetic stir bar, is stirred a solution of 16d in dry toluene. To thissolution, at −78° C., is slowly added DIBAL in hexane. The reactionmixture is stirred for 2 hours and then warned to 0° C. Saturated isadded to the reaction mixture which is then slowly warmed to 25° C.Diluted with water (100 mL), the insoluble precipitate is removed bysuction filtration and the solid is washed with EtOAc (2×25 mL). Theliquid phase is extracted with EtOAc (3×50 mL) and the combined organicphase is dried over MgSO₄ and is concentrated in vacuo to give a yellowsyrup. The product, 16c, must either be used immediately or stored at−70° C. overnight. To a suspension of(4-carboxybutyl)triphenylphosphonium in THF at 0° C. under Nitrogen isadded dropwise a solution of KHMDS in toluene. The resulting deep orangecolored reaction mixture is stirred for 1 hour at 25° C. To the reactionmixture above at −78° C. is added a solution of 16e in THF. The reactionmixture is allowed to warm to 25° C. overnight. The reaction is quenchedwith water at 0° C. and the pH is adjusted to 3.5-4.0 with 1N HCl. Thewater phase is extracted with EtOAc and the combined organic phase isdried over MgSO₄ and is concentrated in vacuo to give a syrup containingcrude acid. To a well stirred solution of acid in and MeOH at 0° C. isadded TMS diazomethane until the reaction mixture keeps a light yellowcolor. The addition of 1 drop of acetic acid, glacial and thin layerchromatography verifies the reaction has gone to completion. Thereaction solution is concentrated in vacuo and is purified via flashchromatography on silica gel eluting with 30% EtOAc in hexanes yielding16f.

e. Methyl 7-(2-Hydroxy-4-(o-bromobenzyloxy)-5-formyl-cyclopentyl)hept-5-enoate (16g): In a round-bottomed flask with a magnetic stir baris placed an amount of the ketal, 16f. To this flask is added asufficient amount of a mixture of 2 parts acetone to 1 part 1N HCl tobring the ketal completely into solution. This material is stirreduntil, by TLC, the starting material is consumed, typically overnight.The crude mixture, containing the product 16g, is extracted with ether,and the ether extract re-esterified in situ with, preferably,TMS-diazomethane. The organic extracts were concentrated under reducedpressure at 0° C. and used immediately without further purification.

f. Dimethyl-3-(2-Fluorophenoxy)-2-oxo-butylphosphonate (16j): In aflame-dried, round-bottomed flask equipped with a stir bar andthermometer is placed dimethylmethyl phosphonate (1.0 equiv.) inanhydrous THF. The solution is cooled to −78° C. and treated withn-butyllithium (1.05 equiv.). The reaction mixture is allowed to stirfor 15 minutes. To this solution is addedmethyl-2-(2-fluorophenoxy)propionate (1.1 equiv.) in anhydrous THF. Themixture is allowed to warm to room temperature over the next 6 hours.The mixture is treated with a saturated solution of ammonium chlorideand extracted with CH₂Cl₂. The organic layer is washed with waterfollowed by brine. The combined aqueous layers are back extracted withCH₂Cl₂ and the organic layers combined, dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure. Purification iseffected by silica gel column chromatography (hexane/ethylacetate/2-propanol 45/50/5 to hexane/ethyl acetate/2-propanol 40/50/10)to yield 1.34 g (70%) ofdimethyl-4-(2-fluorophenyl)-2-oxo-butylphosphonate (16j) as an oil.

g. 11-o-Bromobenzyloxy-16-(2-Fluorophenoxy)-17-trinor-15-oxo-PGF₂αMethyl Ester (16k): In a flame-dried, round-bottomed flask equipped witha magnetic stirbar is placeddimethyl-4-(2-fluorophenyl)-2-oxo-butylphosphonate (16j) (1.43 equiv) inDME and water. To this solution is added lithium bromide (1.65 equiv),triethylamine (1.65 equiv), and (16g) (1.0 equiv). The solution isstirred at room temperature for 48 hours. At this point additionaltriethylamine and water is added and the solution is stirred for anadditional hour. The solution is poured into brine and extracted with 3portions of ethyl acetate. The organic layers are combined, dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure.Purification is effected by silica gel column chromatography(dichloromethane/methanol 19/1) to give11-o-bromobenzyloxy-17-(2-fluorophenyl)-17-trinor-15-oxo-PGF_(2a) methylester (1k) as an oil.

h. 11-o-Bromobenzyloxy-15-(R,S)-16-(2-fluorophenoxy)-17-trinor-PGF_(2a)Methyl Ester (16l): In a flame-dried round-bottomed flask equipped witha stir bar is placed 17-(2-fluorophenyl)-17-trinor-15-oxo-PGF_(2a)methyl ester (16k) (1.0 equiv), cerium trichloride (1.05 equiv) inmethanol. The solution is stirred at room temperature for 5 minutes. Thesolution is cooled to −10° C. and sodium borohydride (1.02 equiv.) inmethanol is added. The solution is stirred at −10° C. for 3 hours. Themixture is treated with water and the pH brought to 6-7 with 1Nhydrochloric acid. The mixture is extracted twice with ethyl acetate,and the organic layers combined, dried over anhydrous MgSO₄, filteredand concentrated under reduced pressure. Purification is effected bysilica gel column chromatography (3% methanol in dichloromethane to 5%methanol in dichloromethane) to give the 15 (R) epimer and the 15 (S)epimer as colorless oils.

i.9,15-bis-tert-Butyldimethylsilyloxy-13,14-dihydro-16-(2-fluorophenoxy)-17-trinor-PGD₂Methyl Ester (16m): In a round-bottomed flask equipped with a magneticstirbar, is stirred a solution of 16l (1 equiv) in CH₂Cl₂. To thissolution is added dropwise at −78° C. 2,6-lutidine (2.9 equiv.) followedby TBDMSOTf (2.8 equiv.). The reaction stirred for 30 minutes at −78° C.and then warmed to 25° C. overnight. The reaction is quenched withwater. The organic layer is washed with water, dried over MgSO₄, andconcentrated in vacuo to give a yellow oil which is subjected to flashchromatography on silica gel eluting with hexanes then 1% MeOH inCH₂Cl₂. The product is then washed with 1N HCl, 0.1N HCl, water, andbrine to give the bis-protected intermediate. This intermediate isplaced in a flame-dried round-bottomed flask equipped with a stir bar.Tri-n-butyl tin hydride is added to Ether and the reaction is stirredfor 24 hours. Quenching with 1N HCL and then back washing the organics 2with with brine. Dry over MgSO₄ and the organic layer is concentratedunder reduced pressure and chromatographed to yield the PGD analog 16m.

j. 11-Oximyl-13,14-dihydro-16-(2-fluorophenoxy)-17-trinor-PGD₂ (16n): Around-bottomed flask equipped with a stirbar is cooled to 0° C. and themethyl ester (16m) and a solution of HF in pyridine are added. Thesolution is allowed to warm to room temperature and followed by TLC.Upon consumption of the starting material, the solution is concentratedand partitioned between ethyl acetate and 0.1% aqueous sodium carbonate.The organic extracts are combined and chromatographed and the crudeproduct is stirred overnight with hydroxylamine and sodium acetate (1:9)in 1:1:3 p-dioxane: water: methanol. The mixture is concentrated underreduced pressure and added is lithium hydroxide monohydrate (1.8 equiv)in a 50/50 THF/water solution. The mixture is stirred at roomtemperature for 6 hours and then diluted with water and acidified to pH2-3 with 1N HCl. The aqueous phase is extracted 3 times with ethylacetate and the organic layers combined. The combined organic layerswere dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure to yield the crude acid. Purification is effected byHPLC to yield an analytical sample of 16n.

Examples 17-28

Examples 17-28 are prepared using substantially the same procedures asthose described in Example 16, substituting the appropriate startingmaterials. The skilled artisan may change temperature, pressure,atmosphere, solvents or the order of reactions as appropriate.Additionally, the skilled artisan may use protecting groups to blockside reactions or increase yields as appropriate. All such modificationscan readily be carried out by the skilled artisan in the art of organicchemistry, and thus are within the scope of the invention.

Example 17

11-Oximyl-16-(2,4-difluorophenylthio)-17-trinor-PGD₂ Methyl Ester

Example 18

11-Oximyl-16-aza-(3,5-difluorophenyl)-17-trinor PGD₂

Example 19

11-Oximyl-16-(2-fluorophenylthio)-17-trinor-PGD₂ Methyl Ester

Example 20

11-Oximyl-16-(4-fluorophenoxy)-16-tetranor PGD₂ Ethyl Ester

Example 21

11-Oximyl-16-(4-fluorophenylthio)-16-tetranor PGD₂

Example 22

11-Oximyl-16-(2-methoxyphenoxy)-16-tetranor PGD₂

Example 23

11-Oximyl-16-(3-methoxyphenoxy)-16-tetranor PGD₂ Isopropyl Ester

Example 24

11-Oximyl-17-oxo-(2-methyl-thienyl)-18-dinor PGD₂ Methyl Ester

Example 25

11-Oximyl-16-((3-trifluoromethyl)phenoxy)-16-tetranor PGD₂ Methyl Ester

Example 26

11-Oximyl-16-(2-methylphenoxy)-16-tetranor PGD₂ Methyl Ester

Example 27

11-Oximyl-16-(3-methylphenoxy)-16-tetranor PGD₂

Example 28

11-Oximyl-16-phenoxy-16-tetranor PGD₂

Example 29

Preparation of 11-Oximyl-13,14-dihydro-16-phenylthio 16-tetranor PGD₁α(29b):

Compound 1i from Example 1 is treated with sodium cyanoborohydride inTHF: acetic acid (1:1) and allowed to react for 2 hours. The mixture isquenched with 1 N HCl and washed with brine twice. The organic layer isdried over magnesium sulfate and reduce under pressure. The resultingoil is chromatographed using 30% ethyl acetate: hexane. Appropriatefractions were combined and reduced to a yellow oil, yielding 29a.Deprotection is accomplished by methods described above, yielding 29b.

Examples 30-34

Examples 30-34 are prepared using substantially the same procedures asthose described in Example 29, substituting the appropriate startingmaterials. The skilled artisan may change temperature, pressure,atmosphere, solvents or the order of reactions as appropriate.Additionally, the skilled artisan may use protecting groups to blockside reactions or increase yields as appropriate. All such modificationscan readily be carried out by the skilled artisan in the art of organicchemistry, and thus are within the scope of the invention.

Example 30

11-Hydroxylamino-13,14-dihydro-16-(3-chlorophenoxy)-16-tetranor -PGD₁

Example 31

11-Hydroxylamino-13,14-dihydro-16-(2,4-difluorophenylthio)-16-tetranorPGD₁ Methyl Ester

Example 32

11-Hydroxylamino-13,14-dihydro-16-aminophenyl-16-tetranor -PGD₁

Example 33

11-Hydroxylamino-13,14-dihydro-16-(4-fluorophenylthio)-16-tetranor PGD₁Ethyl Ester

Example 34

11-Hydroxylamino-13,14-dihydro-16-(4-fluorophenoxy)-16-tetranor PGD₁

Example 35

11-Hydroxylamino-16-phenoxy-16-tetranor-1-tetrazolyl PGD₂

11-oximyl-16-phenoxy-16-tetranor-1-tetrazolyl PGD₂ is prepared usingsubstantially the same procedures as those described in Example 16,substituting the tetrazoyl phosphonium salt for the carboxylate andphenyl for the o-fluorophenyl. To this compound (35a) is added 1.5equiv. of sodium cyanoborohydride in a 1:1 mixture of acetic acid andtetrahydrofuran. The reaction is monitored by TLC. After completeconsumption of starting material, the reaction is diluted with water andexhaustively extracted with EtOAc, yielding the hydroxylamine.

Examples 36-40

Examples 36-40 are prepared using substantially the same procedures asthose described in Example 35, substituting the appropriate startingmaterials. The skilled artisan may change temperature, pressure,atmosphere, solvents or the order of reactions as appropriate.Additionally, the skilled artisan may use protecting groups to blockside reactions or increase yields as appropriate. All such modificationscan readily be carried out by the skilled artisan in the art of organicchemistry, and thus are within the scope of the invention.

Example 36

11-Hydroxylamino-16-phenylthio-16-tetranor -PGD_(2a)

Example 37

11-Hydroxylamino-20-ethoxy- PGD_(2a)

Example 38

11-Methoxylamino-16-(3,5-difluorophenoxy)-16-tetranor PGD_(2a)

Example 39

11-Hydroxylamino-16-(3-thiofuranyl)-17-trinor-PGD_(2a)

Example 40

11-Hydroxylamino-16-((3-trifluoromethyl)phenoxy)-17-trinor PGD_(2a)

Example 41

11-Oximyl-15-methyl-16-2-fluorophenoxy-17-trinor-PGD₂Methyl Ester

Compound 16k from Example 16 is dissolved in dry THF and 1.2 equiv. ofTBDMSOTf and 1.5 equiv. of 2,6 lutidine are added. Standard work-upyields the TBDMS-protected version of 16k, which is dissolved in THF.Addition of the methylcerium nucleophile (1.5 equiv.) (for examples ofcerium chloride-mediated nucleophilic addition see: T. Imamoto, et al.,“Carbon-Carbon Bond Forming Reactions Using Cerium Metal or Organocerium(III) Reagents”, J. Org. Chem. Vol. 49 (1984) p. 3904-12; T. Imamoto, etal., “Reactions of Carbonyl Compounds with Grignard Reagents in thePresence of Cerium Chloride”, J. Am. Chem. Soc. Vol. 111 (1989) p.4392-98; and references cited therein) gives the product S41c, whichafter purification is dissolved in liquid ammonia and a sufficientamount of lithium metal is added to effect deprotection of the benzylether. After purification, the deprotected S41c is condensed withhydroxylamine as described in Example 1 and deprotected to yield thetitle compound, S41d.

Examples 42-43

Examples 42-43 are prepared using substantially the same procedures asthose described in Example 41, substituting the appropriate startingmaterials. The skilled artisan may change temperature, pressure,atmosphere, solvents or the order of reactions as appropriate.Additionally, the skilled artisan may use protecting groups to blockside reactions or increase yields as appropriate. All such modificationscan readily be carried out by the skilled artisan in the art of organicchemistry, and thus are within the scope of the invention.

Example 42

11-Oximyl-15-ethyl-17-phenoxy-18-dinor-PGD₂

Example 43

3-oxo-11-Oximyl-13,14-dihydro-15-methyl-16-phenoxy-16-tetranor -PGD_(1α)

Example 44

3-oxo-11-Hydroxylamino-13,14-dihydro-15-methyl-16-phenoxy-16-tetranor-PGD_(1α)

To a 50 mL round bottom flask is3-oxo-11-oximyl-13,14-dihydro-15-methyl-16-phenoxy-17-trinor-PGD₂ (fromExample 43) and 1.5 equiv. of sodium cyanoborohydride in a 1:1 mixtureof acetic acid and tetrahydrofuran. The reaction is monitored by TLC.After complete consumption of starting material, the reaction is dilutedwith water, the pH is adjusted to 3.0, and exhaustively extracted withEtOAc, yielding the title hydroxylamine-containing PGF analog.

Example 45

11-oximyl-15-methyl-15-deoxy-15-methamino-16-2-fluorophenoxy-16-tetranor-PGD₂Methyl Ester

Compound 16k from Example 16 is dissolved in dry THF and 1.2 equiv. ofTBDMSTf and 1.5 equiv. of 2,6 lutidine are added. Standard work-upyields the TBDMS-protected version of 16k, which is dissolved in THF andcondensed with methylamine to give the intelmediate imine. Addition ofthe methylcerium nucleophile (˜1.5 equiv.) (for examples of ceriumchloride-mediated nucleophilic addition see: T. Imamoto, et al.,“Carbon-Carbon Bond Forming Reactions Using Cerium Metal or Organocerium(III) Reagents”, J. Org. Chem. Vol. 49 (1984) p. 3904-12; T. Imamoto, etal., “Reactions of Carbonyl Compounds with Grignard Reagents in thePresence of Cerium Chloride”, J. Am. Chem. Soc. Vol. 111 (1989) p.4392-98; and references cited therein) gives the product S45b, whichafter purification is dissolved in THF and a sufficient amount oftri-nbutyl tin hydride is added to effect the oxidative removal of thebenzyl ether. After purification, S45c is condensed with hydroxylamineas described in Example 16 and deprotected to yield the title compound,S45d.

Example 46

11-Hydroxylamino-15-methyl-15-deoxy-15-methylamino-16-2-fluorophenoxy-16-tetranor-PGF_(2a)Methyl Ester

To a 50 mL round bottom flask is charged11-oximyl-15-methyl-15-deoxy-15-methamino-16-o-fluorophenoxy-17-trinor-PGD₂methyl ester (Example 45) and 1.5 equiv. of sodium cyanoborohydride in a1:1 mixture of acetic acid and tetrahydrofuran. The reaction ismonitored by TLC. After complete consumption of starting material, thereaction is diluted with water and exhaustively extracted with EtOAc,yielding the title hydroxylamine-containing PGF analog.

Example 47

Preparation of11-Oximyl-13,14-dihydro-16-((3-trifluoromethyl)phenoxy)-16-tetranor-PGD₁1-hydroxamicAcid:

In a flame-dried 25 mL round-bottomed flask equipped with a magneticstirbar is placed 11-oximyl-13,14-dihydro-16-((3-trifluoromethyl)phenoxy)-17-trinor-PGD₁ methyl ester (Example 12) (1.0 equiv.) inmethanol. To this solution is added hydroxylamine in methanol (1.25equiv.). The solution is stirred for 18 hours. The solution is thentreated with 1N hydrochloric acid and thrice extracted with ethylacetate. The organic layer is washed with saturated aqueous sodiumchloride, dried over anhydrous MgSO₄, filtered and concentrated underreduced pressure. The residue is purified by chromatography to give11-oximyl-13,14-dihydro-16-((3-trifluoromethyl)phenoxy)-16-tetranor-PGD₁ 1-hydroxamic acid.

Example 48

Example 48 is prepared using substantially the same procedures as thosedescribed in Example 47, substituting the appropriate startingmaterials. The skilled artisan may change temperature, pressure,atmosphere, solvents or the order of reactions as appropriate.Additionally, the skilled artisan may use protecting groups to blockside reactions or increase yields as appropriate. All such modificationscan readily be carried out by the skilled artisan in the art of organicchemistry, and thus are within the scope of the invention.

Example 48

11-Oximyl-16-phenoxy-17-trinor-PGD₂ 1-N-methanesulfonamide

Compositions

Compositions of the subject invention comprise a safe and effectiveamount of the subject compounds, and a pharmaceutically-acceptablecarrier. As used herein, “safe and effective amount” means an amount ofa compound sufficient to significantly induce a positive modification inthe condition to be treated, but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical judgment. A safe and effective amount of a compound will varywith the particular condition being treated, the age and physicalcondition of the patient being treated, the severity of the condition,the duration of the treatment, the nature of concurrent therapy, theparticular pharmaceutically-acceptable carrier utilized, and likefactors within the knowledge and expertise of the attending physician.

In addition to the compound, the compositions of the subject inventioncontain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a subject. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the compound, and witheach other, in a manner such that there is no interaction which wouldsubstantially reduce the pharmaceutical efficacy of the compositionunder ordinary use situations. Pharmaceutically-acceptable carriersmust, of course, be of sufficiently high purity and sufficiently lowtoxicity to render them suitable for administration to the subject beingtreated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as cornstarch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, cellulose acetate; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid,magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil,cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma;polyols such as propylene glycol, glycerin, sorbitol, mannitol, andpolyethylene glycol; alginic acid; emulsifiers, such as the Tweens®;wetting agents such as sodium lauryl sulfate; coloring agents; flavoringagents, excipients; tableting agents; stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with a compound is basically determined by the way thecompound is to be administered. The compounds of the present inventionmay be administered systemically. Routes of administration includetransdermal; oral; parenterally, including subcutaneous or intravenousinjection; topical; and/or intranasal.

The appropriate amount of the compound to be used may be determined byroutine experimentation with animal models. Such models include, but arenot limited to the intact and ovariectomized rat models, the ferret,canine, and non human primate models as well as disuse models.

Preferred unit dosage forms for injection include sterile solutions ofwater, physiological saline, or mixtures thereof. The pH of saidsolutions should be adjusted to about 7.4. Suitable carriers forinjection or surgical implants include hydrogels, controlled- orsustained release devises, polylactic acid, and collagen matrices.

Suitable pharmaceutically-acceptable carriers for topical applicationinclude those suited for use in lotions, creams, gels and the like. Ifthe compound is to be administered perorally, the preferred unit dosageform is tablets, capsules and the like. The pharmaceutically-acceptablecarriers suitable for the preparation of unit dosage forms for oraladministration are well-known in the art. Their selection will depend onsecondary considerations like taste, cost, and shelf stability, whichare not critical for the purposes of the subject invention, and can bemade without difficulty by those skilled in the art.

Methods of Use

The compounds of the present invention are useful in treating manymedical disorders, including for example, ocular disorders,hypertension, fertility control, nasal congestion, neurogenic bladderdisorder, gastrointestinal disorders, dermatological disorders, andosteoporosis.

The compounds of the present invention are useful in increasing (1) bonevolume and trabecular number through formation of new trabeculae, (2)bone mass while maintaining a normalized bone turnover rate, and/or (3)formation at the endosteal surface without removing bone from theexisting cortex. Thus, these compounds are useful in the treatment andprevention of bone disorders.

The preferred routes of administration for treating bone disorders aretransdermal and intranasal. Other preferred routes of administrationinclude rectal. sublingual, and oral.

The dosage range of the compound for systemic administration is fromabout 0.01 to about 1000 μg/kg body weight, preferably from about 0.1 toabout 100 μg/kg per body weight, most preferably form about 1 to about50 μg/kg body weight per day. The transdermal dosages will be designedto attain similar serum or plasma levels, based upon techniques known tothose skilled in the art of pharmacokinetics and transdermalformulations. Plasma levels for systemic administration are expected tobe in the range of 0.01 to 100 nanograms/mi, more preferably from 0.05to 50 ng/ml, and most preferably from 0.1 to 10 ng/ml. While thesedosages are based upon a daily administration rate, weekly or monthlyaccumulated dosages may also be used to calculate the clinicalrequirements.

Dosages may be varied based on the patient being treated, the conditionbeing treated, the severity of the condition being treated, the route ofadministration, etc. to achieve the desired effect.

The compounds of the present invention are also useful in decreasingintraocular pressure. Thus, these compounds are useful in the treatmentof glaucoma. The preferred route of administration for treating glaucomais topically.

COMPOSITION AND METHOD EXAMPLES

The following non-limiting examples illustrate the subject invention.The following composition and method examples do not limit theinvention, but provide guidance to the skilled artisan to prepare anduse the compounds, compositions and methods of the invention. In eachcase other compounds within the invention may be substituted for theexample compound shown below with similar results. The skilledpractitioner will appreciate that the examples provide guidance and maybe varied based on the condition being treated and the patient.

Example A

Pharmaceutical compositions in the form of tablets are prepared byconventional methods, such as mixing and direct compaction, formulatedas follows:

Ingredient Quantity (mg per tablet) Compound of Example 1 5Microcrystalline Cellulose 100 Sodium Starch Glycollate 30 MagnesiumStearate 3

When administered orally once daily, the above composition substantiallyincreases bone volume in a patient suffering from osteoporosis.

Example B

Pharmaceutical compositions in liquid form are prepared by conventionalmethods, formulated as follows:

Ingredient Quantity Compound of Example 32 1 mg Phosphate bufferedphysiological saline 10 ml Methyl Paraben 0.05 ml

When 1.0 ml of the above composition is administered subcutaneously oncedaily, the above composition substantially increases bone volume in apatient suffering from osteoporosis.

Example C

Topical pharmaceutical compositions for lowering intraocular pressureare prepared by conventional methods and formulated as follows:

Ingredient Amount (wt %) Compound of Example 1 0.004 Dextran 70 0.1Hydroxypropyl methylcellulose 0.3 Sodium Chloride 0.77 Potassiumchloride 0.12 Disodium EDTA (Edetate disodium) 0.05 Benzalkoniumchloride 0.01 HCL and/or NaOH pH 7.2-7.5 Purified water q.s. to 100%

While particular embodiments of the subject invention have beendescribed, it would be obvious to those skilled in the art that variouschanges and modifications to the compositions disclosed herein can bemade without departing from the spirit and scope of the invention. It isintended to cover, in the appended claims, all such modifications thatare within the scope of this invention.

What is claimed is:
 1. A compound having the structure:

characterized in that (a) R₁ is CO₂H, C(O)NHOH, CO₂R₇, CH₂OH, S(O)₂R₇,C(O)NHR₇, C(O)NHS(O)₂R₇, or tetrazole; characterized in that R₇ isalkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclicheterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclicheteroaromatic ring; (b) W is O, NH, S, S(O), S(O)₂, or (CH₂)_(m);characterized in that m is an integer from 0 to about 3; (c) R₂ is H andR₃ is H or lower alkyl, or R₂ and R₃ together form a covalent bond; (d)R₄ is H, alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring,monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, ormonocyclic heteroaromatic ring; (e) each R₅ is independently selectedfrom the group consisting of H, CH₃, and C₂H₅; (f) X is NHR₈ or OR₈,characterized in that each R₈ is independently selected from the groupconsisting of H, acyl, alkyl, heteroalkyl, monocyclic carbocyclicaliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclicaromatic ring, and monocyclic heteroaromatic ring; (g) each R₆ isindependently selected from the group consisting of H, CH₃, C₂H₅, OR₈,and NHR₈; (h) Y is O, NHR₈, S, S(O), or S(O)₂, provided no carbon hasmore than one heteroatom attached to it; (i) Z is H, methyl, monocycliccarbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring,monocyclic aromatic ring, monocyclic heteroaromatic ring, bicycliccarbocyclic aliphatic ring, bicyclic heterocyclic aliphatic ring,bicyclic aromatic ring, or bicyclic heteroaromatic ring, provided thatwhen Y is S, S(O), or S(O)₂ and Z is H, q is at least 1; (j) a and b areindependently selected from the group consisting of single bond, cisdouble bond, and trans double bond; (k) p is an integer from 1 to 5, qis an integer from 0 to 5, and p+q is 1 to 5; and any optical isomer,diastereomer, enantiomer of the above structure or apharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, orimide thereof.
 2. The compound of claim 1 wherein R₁ is CO₂H, C(O)NHOH,CO₂R₇, C(O)NHS(O)₂R₇, or tetrazole.
 3. The compound of claim 2 wherein Wis O or (CH₂)_(m).
 4. The compound of claim 3 wherein R₄ and R₅ are eachH and X is OH.
 5. The compound of claim 4 wherein R₁ is CO₂H or CO₂R₇.6. The compound of claim 5 wherein W is (CH₂)₁.
 7. The compound of claim6 wherein p+q is 1 or
 2. 8. The compound of claim 7 wherein Z ismonocyclic aromatic ring or monocyclic heteroaromatic ring.
 9. Thecompound of claim 6 wherein p+q is 3 to
 5. 10. The compound of claim 9wherein Z is H or methyl.
 11. The compound of claim 8 wherein a is a cisdouble bond and b is a trans double bond.
 12. The compound of claim 10wherein a is a cis double bond and b is a trans double bond.
 13. Thecompound of claim 11 wherein R₂ and R₃ are both H.
 14. The compound ofclaim 11 wherein R₂ and R₃ together form a double bond.
 15. The compoundof claim 12 wherein R₂ and R₃ are both H.
 16. The compound of claim 12wherein R₂ and R₃ together form a double bond.
 17. A method of treatinga human or other animal subject having a bone disorder, said methodcomprising administering to said subject a compound according to thestructure:

wherein (a) R₁ is CO₂H, C(O)NHOH, CO₂R₇, CH₂OH, S(O)₂R₇, C(O)NHR₇,C(O)NHS(O)₂R₇, or tetrazole; wherein R₇ is alkyl, heteroalkyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; (b) Wis O, NH, S, S(O), S(O)₂, or (CH₂)_(m); wherein m is an integer from 0to about 3; (c) R₂ is H and R₃ is H or lower alkyl, or R₂ and R₃together form a covalent bond; (d) R₄ is H, alkyl, heteroalkyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; (e)each R₅ is independently selected from the group consisting of H, CH₃,and C₂H₅; (f) X is NHR₈ or OR₈, wherein each R₈ is independentlyselected from the group consisting of H, acyl, alkyl, heteroalkyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, and monocyclic heteroaromatic ring; (g)each R₆ is independently selected from the group consisting of H, CH₃,C₂H₅, OR₈, and NHR₈; (h) Y is O, NHR₈, S, S(O), or S(O)₂, provided nocarbon has more than one heteroatom attached to it; (i) Z is H, methyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, monocyclic heteroaromatic ring, bicycliccarbocyclic aliphatic ring, bicyclic heterocyclic aliphatic ring,bicyclic aromatic ring, or bicyclic heteroaromatic ring, provided thatwhen Y is S, S(O), or S(O)₂ and Z is H, q is at least 1; (j) a and b areindependently selected from the group consisting of single bond, cisdouble bond, and trans double bond; (k) p is an integer from 1 to 5, qis an integer from 0 to 5, and p+q is 1 to 5; and any optical isomer,diastereomer, enantiomer of the above structure or apharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, orimide thereof.
 18. The method of claim 17 wherein said disorder isosteoporosis.
 19. The method of claim 18 wherein in osteoporosis ispost-menopausal.
 20. The method of claim 18 wherein in osteoporosis iscortico-steroid induced.
 21. The method of claim 17 wherein said bonedisorder is osteopenia.
 22. The method of claim 17 wherein said bonedisorder is a bone fracture.
 23. The method of claim 17 wherein saidcompound is administered orally.
 24. The method of claim 17 wherein saidcompound is administered transdermally.
 25. The method of claim 17wherein said compound is administered intranasally.
 26. A method oftreating glaucoma, said method comprising administering to a human orother animal a safe and effective amount of a compound according to thestructure:

wherein (a) R₁ is CO₂H, C(O)NHOH, CO₂R₇, CH₂OH, S(O)₂R₇, C(O)NHR₇,C(O)NHS(O)₂R₇, or tetrazoie; wherein R₇ is alkyl, heteroalkyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; (b) Wis O, NH, S, S(O), S(O)₂, or (CH₂)_(m); wherein m is an integer from 0to about 3; (c) R₂ is H and R₃ is H or lower alkyl, or R₂ and R₃together form a covalent bond; (d) R₄ is H, alkyl, heteroalkyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; (e)each R₅ is independently selected from the group consisting of H, CH₃,and C₂H₅; (f) X is NHR₈ or OR₈, wherein each R₈ is independentlyselected from the group consisting of H, acyl, alkyl, heteroalkyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, and monocyclic heteroaromatic ring; (g)each R₆ is independently selected from the group consisting of H, CH₃,C₂H₅, OR₈, and NHR₈; (h) Y is O, NHR₈, S, S(O), or S(O)₂, provided nocarbon has more than one heteroatom attached to it; (i) Z is H, methyl,monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphaticring, monocyclic aromatic ring, monocyclic heteroaromatic ring, bicycliccarbocyclic aliphatic ring, bicyclic heterocyclic aliphatic ring,bicyclic aromatic ring, or bicyclic heteroaromatic ring, provided thatwhen Y is S, S(O), or S(O)₂ and Z is H, q is at least 1; (j) a and b areindependently selected from the group consisting of single bond, cisdouble bond, and trans double bond; (k) p is an integer from 1 to 5, qis an integer from 0 to 5, and p+q is 1 to 5; and any optical isomer,diastereomer, enantiomer of the above structure or apharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, orimide thereof.
 27. The method of claim 26 wherein said compound isadministered topically.